Background: Aromatase inhibitors are more effective neoadjuvant endocrine therapy than tamoxifen and preoperative aromatase inhibitor treatment is gaining acceptance as a non-toxic approach to improving surgical outcomes in older postmenopausal women with estrogen receptor positive (ER+) tumors who are not eligible for breast conserving surgery. This clinical setting opens a significant opportunity to investigate the molecular basis for responsiveness to aromatase inhibitor therapy in a situation where the primary tumor can be repeatedly accessed for gene expression profiling and predictive biomarker analysis. Hypothesis: Gene expression profiling can distinguish between ER+ positive, aromatase inhibitor sensitive breast cancer from ER+, aromatase inhibitor resistant disease. Plan of investigation: Ninety postmenopausal patients with ER+ breast cancer requiring neoadjuvant treatment will receive four months preoperative letrozole in a multi-center Phase 2 study. Tumor biopsies will be obtained before treatment and subjected to Affymetrix GeneChip analysis. Supervised analyses, based on structured factor regression modeling and class membership predictor algorithms, will be used to search for gene expression profiles that predict clinical response, radiological response and a decline in proliferation with treatment. The expression patterns of the most predictive genes will be confirmed by in situ mRNA hybridization. Post-treatment samples taken at one month and at surgery will be used to further investigate the nature of ER+ tumors that do not respond to estrogen deprivation treatment. Differences in the changes in gene expression profiles between responding and non-responding tumors will provide insight into the molecular basis for this important clinical problem. Long-term objectives: To improve long-term outcomes and reduce the toxicity of breast cancer treatment in older patients with ER+ breast cancer by developing more effective endocrine therapy regimens. Accurate predictive biomarkers for aromatase inhibitor therapy would allow: a) increased use of neoadjuvant endocrine therapy as a non-toxic means to improve surgical outcomes, b) the identification of patients with aromatase inhibitor-sensitive disease in whom adjuvant chemotherapy can be safely avoided and c) lead to insights into aromatase inhibitor resistance that can be addressed by future clinical trials.